MNK1/2-IN-7 (compound 20j) serves as an orally administered inhibitor targeting MNK1/2, known for its anticancer properties and hERG safety. It also blocks the phosphorylation of eIF4E, thereby disrupting the MNK/eIF4E signaling pathway and reducing cancer cell growth. Additionally, MNK1/2-IN-7 synergizes effectively with Ibrutinib. [15] [1]

MNK1:4.4 nM, MNK2:4 nM

MNK1/2-IN-7 (1.25-5 μM; 24 h) inhibits the phosphorylation of eIF4E in Hela cells (IC 50 =90.5 nM) and reduces the phosphorylation of eIF4E and 4E-BP1 in A549 cells [1]. This compound exhibits stability in human, canine, and rat liver microsomes, with half-lives of 62.6 min, >120 min, and 64.6 min, respectively [1]. Western Blot Analysis [1] was performed on A549 cell line at concentrations of 1.25 μM, 2.5 μM, and 5 μM for 24 hours, showing a downregulation in the phosphorylation of eIF4E and 4E-BP1.

MNK1/2-IN-7 administered orally at a single dose of 5 mg/kg exhibits acceptable exposure and bioavailability in rats. When given at 10 mg/kg orally for 17 days in a DOHH2 xenograft mouse model, it effectively reduces tumor size without affecting body weight, and shows synergistic effects with Ibrutinib [1]. Pharmacokinetic analysis in SD rats revealed the following: Route, Dose (mg/kg), T 1/2 (h), T max (h), C max (μg/mL), AUC 0-t (h·μg/mL), AUC 0-∞ (h·μg/mL), Cl (mL/h/kg), F (%)—i.v. 1, 13.8, 0.083, 1.3, 10.0, 14.4, 70.2; p.o. 5, >24, 6, 1.5, 23.3, NA, 46.86. In the GCB-DLBCL DOHH2 xenograft tumors model in mice, a dosage of 10 mg/kg administered once daily for 17 days, or in combination with 3 mg/kg Ibrutinib, led to tumor regression and achieved a greater TGI value of 54% for the combination group compared to single-agent treatment.